Role of the Epitranscriptome in Cancer More than 600,000 Americans will die this year from cancer. One limitation in treating this devastating disease is the lack of ?druggable? targets for therapeutic intervention. Over the last thirty years much work has been done on understanding how epigenetic changes including DNA methylation, and histone modifications influence gene expression and contribute to cancer, and drugs targeting certain DNA or histone methyltransferases are used in the clinic. It is emerging that mammalian messenger RNAs (mRNAs) are also subject to various posttranscriptional modifications including methylation but the relevance of this pathway in cancer has not yet been examined. The ambitious goal of this pioneering proposal is to explore the relevance of mRNA methylation in cancer and to establish the ?epitranscriptome? as a new and effective cancer therapeutic target. To accomplish this we will map the epitranscriptome in a panel of primary human lung- and colon adenocarcinomas as well as matched normal tissues, explore the mechanism and function of altered mRNA methylation in human cancer cells and mouse cancer models, and perform high-throughput screening to identify small molecules that can specifically inhibit certain mRNA methyltransferases. The molecules we identify will be tested in cancer cells and mouse xenografts for their ability to restore mRNA methylation as a means to suppress oncogene expression and cancer growth. This work promises to transform the field of cancer medicine by establishing the epitranscriptome as a novel therapeutic target and could lead to more effective treatments for lung, colon and other tumor types.